Novel sulfonation method for zonisamide intermediate in zonisamide synthesis and their novel crystal forms

ABSTRACT

The present invention relates to a novel sulfonation of an intermediate of zonisamide. The sulfonation processes using chlorosulfonic acid as well as acetic anhydride and sulfuric acid in an organic solvent are disclosed. Crystalline forms of benzisoxazole methane sulfonic acid (BOS-H) and its salts (BOS-Na, BOS-Ca, and BOS-Ba) and their novel preparation processes are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefits under 35 U.S.C. § 1.119(e)of Provisional Application Serial No. 60/316,109 filed Aug. 30, 2001 and60/344,439 filed Oct. 24, 2001, the disclosure of which is incorporatedby reference in its entirety herein.

FIELD OF THE INVENTION

[0002] The field of the invention is the sulfonation of a zonisamideintermediate and crystalline forms of the zonisamide intermediate in theform of acid and metallic salts. Within that field, the presentinvention relates most particular to novel sulfonation processes forpreparing the zonisamide intermediate of benzisoxazole acetic acid andthe crystalline forms thereof.

BACKGROUND OF THE INVENTION

[0003] Zonisamide is known as 1,2-benzisoxazole-3-methane sulfonamide or3-(sulfamoylmethyl)-1,2-benzisoxazole. It has the following chemicalformula:

[0004] Zonisamide is currently available as an anti-epileptic agentwhich possesses anti-convulsant and anti-neurotoxic effects.

[0005] Several routes for zonisamide synthesis have been described inthe literature. Two of these synthesis routes start from4-hydroxy-coumarin via benzisoxazole acetic acid (hereinafter; BOA) andsodium salt of benzisoxazole methane sulfonic acid (hereinafter;BOS-Na).

[0006] Scheme 1 represents the first route for zonisamide synthesis. Inthis route, the zonisamide intermediate (BOA) is brominated followed bysubstitution of the bromine by sodium sulfite to give the advancedintermediate sodium salt of BOS (BOS-Na) as shown as follows:

[0007] The sulfonation reaction of the zonisamide intermediate (i.e.,BOA) with chlorosulfonic acid (in this case the reagent used also is thereaction solvent) gives the disulfonated-benzisoxazole-derivative(S-BOS) as the main reaction by-product. The synthetic method of theroute shown in scheme 1 is a difficult method due to the greatsensitivity of the reaction product.

[0008] The second method described in literature for zonisamidepreparation includes the preparation of BOA starting from4-hydroxy-coumarin, followed by the sulfonation reaction of BOA to BOS.The sulfonation reaction of the zonisamide intermediate (i.e., BOA) maybe carried out with chlorosulfonic acid. The reagent chlorosulfonic acidis used in a large excess and it is also the reaction solvent. Thereactions of this synthetic method are shown in scheme 2:

[0009] When the reaction is conducted in chlorosulfonic acid, thesulfonation is not selective. Disulfonated-benzisoxazole derivateive(S-BOS) is a main product of the reaction.

[0010] The synthetic pathway via the sulfonation reaction of BOAcomprises two steps lesser as compared to the synthetic pathway via thebromination reaction. In addition, the sulfonation reaction requires alarge amount of chlorosulfonic acid which poses undesirableenvironmental problems.

[0011] U.S. Pat. No. 4,172,896 by Uno H. et al. (assigned to DainipponPharmaceutical Co.) describes the preparation of zonisamide using thesulfonating agent chlorosulfonic acid: dioxane complex. A similarreagent (SO₃: dioxane complex) is known in the literature and wassuccessfully used for the selective sulfonation of the aromatic ketones.Chlorosulfonic acid:dioxane is a selective sulfonating reagent and thedisulfonated side products is obtained in a low quantity. The reactionis shown in scheme 3.

[0012] Although the sulfonation method using chlorosulfonic acid:dioxane complex is selective, this method is not safe because of theserious environmental problem of the dioxane present in the reactionwaste.

[0013] There is a continuous need to improve the sulfonation method thatis both convenient and environmentally safe. The present inventionprovides an unexpected novel sulfonation process to prepare theintermediate of zonisamide.

[0014] Neither patents have characterized the existence of anycrystalline forms of this product. There is a continuing need toinvestigate crystalline forms of BOS which can provide usefulintermediates for zonisamide synthesis.

[0015] We found that the product of the sulfonation reaction (BOS) maybe isolated as sulfonic acid type compound (BOS-H) or as its salt(metallic salts). Not depending on the product type form, the reactionmixture is usually treated with water allowing the isolation of theproduct with variable water content. These compounds have the tendencyto give hydrates.

[0016] Furthermore, it is generally known that alkyl- and aryl-sulfonicacids and their salts can exist as hydrated form (C. M. Suter in “TheOrganic Chemistry of Sulfur”, J. Wiley, N.Y., 1946). The widely-knownreagent p-toluene-sulfonic acid can exist as monohydrate. It isnecessary to develop another method for preparation of the sodium saltof BOS.

SUMMARY OF THE INVENTION

[0017] According to one aspect, the present invention provides asulfonation process for preparing benzisoxazole methane sulfonic acid(BOS).

[0018] Preferably, anhydride and sulfuric acid are employed in preparingbenzisoxazole methane sulfonic acid (BOS) in a sulfonation process.

[0019] According to another aspect, the present invention provides asulfonation process for preparing benzisoxazole methane sulfonic acid(BOS) employing chlorosulfonic acid in an organic solvent.

[0020] According to another aspect, the present invention provides aprocess for preparing an intermediate of zonisamide, comprising thesteps of:

[0021] a) preparing a mixture of chlorosulfonic acid and an organicsolvent;

[0022] b) adding benzisoxazole acetic acid to the mixture;

[0023] c) heating the mixture; and

[0024] d) isolating the intermediate of zonisamide.

[0025] According to another aspect, the present invention provides asulfonation process for preparing benzisoxazole methane sulfonic acid(BOS) employing acyl-sulfates or in situ prepared acyl-sulfates. In situprepared acyl-sulfates may be obtained from anhydrides and sulfuric acid(H₂SO₄), acyl-halides and H₂SO₄, or carboxylic acids and H₂SO₄.

[0026] Most preferably, acetic anhydride and sulfuric acid are employedin preparing benzisoxazole methane sulfonic acid in a sulfonationprocess.

[0027] According to another aspect, the present invention provides aprocess for preparing an intermediate of zonisamide, comprising thesteps of:

[0028] a) preparing an acyl sulfate in a solution;

[0029] b) adding benzisoxazole acetic acid to the solution wherein thebenzisoxazole acid is sulfonated by the acyl sulfate to form theintermediate of zonisamide;

[0030] c) heating the solution; and

[0031] d) isolating the intermediate of zonisamide.

[0032] According to another aspect, the present invention a process forpreparing an intermediate of zonisamide, comprising the steps of:

[0033] a) preparing a mixture of benzisoxazole acetic acid and ananhydride in a solvent to form a mixture;

[0034] b) preparing an acyl sulfate in the mixture wherein thebenzisoxazole acid is sulfonated by the acyl sulfate to form theintermediate of zonisamide;

[0035] c) heating the mixture; and

[0036] d) isolating the intermediate of zonisamide.

[0037] According to another aspect, the present invention providesbenzisoxazole methane sulfonic acid substantially free of disulfonatedbenzisoxazole derivatives.

[0038] According to another aspect, the present invention provideszonisamide substantially free of disulfonated benzisoxazole derivatives.

[0039] According to another aspect, the present invention provideszonisamide substantially free of impurities and without the use ofdioxane.

[0040] The present invention generally relates to the crystalline formsof benzisoxazole methane sulfonic acid (BOS-H) and its salts.

[0041] The present invention provides the crystalline forms of BOS witha metal cation. Preferably, the present invention provides thecrystalline forms of BOS-Na, BOS-Ca, and BOS-Ba. Other metallic saltsinclude, but not limited to, potassium, magnesium, lithium, manganese,cobalt, iron, copper, nickel, zinc, silver and the like.

[0042] The present invention relates to the zonisamide intermediate BOSin the form of acid and metallic salts which are useful in thezonisamide synthesis.

[0043] The present invention provides the hydrated crystalline forms ofBOS-H and its salts as intermediates in the zonisamide synthesis.

[0044] The present invention provides a novel crystal form of BOS-NaForm I, characterized by an X-Ray Powder Diffraction (XRD) having themost characteristic peaks at about 5.0, 17.3, 18.0, 18.6, and 19.7±0.2degrees two theta.

[0045] The present invention provides a novel crystal form of BOS-NaForm I, characterized by an X-Ray Powder Diffraction (XRD) having themain peaks at about 5.0, 15.7, 16.5, 17.3, 18.6, 19.1, 19.7, 21.5, 22.8,23.2, 23.5 and 24.3±0.2 degrees two theta.

[0046] The present invention provides a novel crystal form of BOS-NaForm I, characterized by a Furier Transform Infra Red Spectroscopy(FTIR) spectrum having the most characteristic peaks at about 3546,3485, 3440, 1641, 669 and 593 cm⁻¹.

[0047] The present invention provides a novel crystal form of BOS-NaForm I, characterized by a Furier Transform Infra Red Spectroscopy(FTIR) spectrum having the following peaks at about 3546, 3485, 3440,1612, 1513, 1439, 1410, 1382, 1234, 1199, 1048, 918, 855, 760, 669 and593 cm⁻¹.

[0048] The present invention provides a novel crystal form of BOS-NaForm I having a water content of about 7%.

[0049] The present invention provides a novel crystal form of BOS-NaForm II, characterized by an X-Ray Powder Diffraction (XRD) having themain peaks at about 5.3, 16.6, 21.3 and 26.7±0.2 degrees two theta.

[0050] The present invention provides a novel crystal form of BOS-NaForm II, characterized by an X-Ray Powder Diffraction (XRD) having themost characteristic peaks at about 5.3, 15.9, 16.6, 21.3 and 26.7±0.2degrees two theta.

[0051] The present invention provides a novel crystal form of BOS-NaForm II, characterized by a Furier Transform Infra Red Spectroscopy(FTIR) spectrum having the following peaks at about 3597, 3535, 3496,3067, 2998, 2951, 1606, 1516, 1438, 1382, 1213, 1064, 1055, 743, 663,588, 541 and 522 cm⁻¹.

[0052] The present invention provides a novel crystal form of BOS-NaForm II having a water content of about 1.8%.

[0053] The present invention provides a novel crystal form of BOS-NaForm II, characterized by an X-Ray Powder Diffraction (XRD) having themost characteristic peaks at about 5.0, 5.3, and 17.8±0.2 degrees twotheta.

[0054] The present invention provides a novel crystal form of BOS-NaForm III, characterized by an X-Ray Powder Diffraction (XRD) having themain peaks at about 5.0, 5.3, 15.7, 17.8 and 21.4±0.2 degrees two theta.

[0055] The present invention provides a novel crystal form of BOS-NaForm III, characterized by a Furier Transform Infra Red Spectroscopy(FTIR) spectrum having the most characteristic peaks at about 3604,1065, 812 and 696 cm⁻¹.

[0056] The present invention provides a novel crystal form of BOS-NaForm m, characterized by a Furier Transform Infra Red Spectroscopy(FTIR) spectrum having the following peaks at about 3604, 3495, 3067,2998, 2951, 1605, 1516, 1438, 1382, 1215, 1136, 1065, 1052, 777, 747,696, 588 and 521 cm⁻¹.

[0057] The present invention provides a novel crystal form of BOS-NaForm V, characterized by an X-Ray Powder Diffraction (XRD) having themain peaks at about 6.7, 10.9, 16.1, 21.0, 21.2 and 22.2±0.2 degrees twotheta.

[0058] The present invention provides a novel crystal form of BOS-NaForm V, characterized by a Furier Transform Infra Red Spectroscopy(FTIR) spectrum having the most characteristic peaks at about 3601,3520, 1587, 1055, 793, and 753 cm⁻¹.

[0059] The present invention provides a novel crystal form of BOS-BaForm V having a water content of less than about 1.5%.

[0060] The present invention provides a novel crystal form of BOS-BaForm I, characterized by the following X-Ray Diffraction main peaks atabout 5.2, 10.4, 12.0, 13.8, 15.6, 17.0, 23.9 and 25.4±0.2 degrees twotheta.

[0061] The present invention provides a novel crystal form of BOS-BaForm I, characterized by a Furier Transform Infra Red Spectroscopy(FTIR) spectrum having the following peaks at about 3544, 3491, 2985,2943, 1626, 1610, 1509, 1437, 1383, 1369, 1223, 1209, 1175, 1153, 1055,1043, 911, 869, 752, 651, 603, 543 and 511 cm⁻¹.

[0062] The present invention provides a novel crystal form of BOS-BaForm I having a water content about 3.5%.

[0063] The present invention provides a novel crystal form of BOS-CaForm I, characterized by having the following X-Ray Diffraction mainpeaks at about 5.4, 11.7, 16.0, 16.7, 17.7, 18.1, 19.1, 20.8, 24.5, 24.9and 29.2±0.2 degrees two theta.

[0064] The present invention provides a novel BOS-H monohydrate Form I,characterized by having the following X-Ray Diffraction main peaks atabout 13.8, 14.4, 17.4, 17.8, 21.8, 22.2, 25.8, 27.8±0.2 degrees twotheta.

[0065] The present invention provides a novel BOS-H monohydrate Form Ihaving a water content about 7.6%.

[0066] The present invention provides a novel process for preparing aBOS-H Form I. The present invention further provides a process ofpreparing a BOS-H Form I, comprising the steps of: 1) preparing amixture of chlorosulfonic acid in an organic solvent; 2) adding BOA tothe mixture; 3) treating the mixture with NaOH to raise pH; and 4)isolating the BOS-H Form I.

[0067] The present invention provides a novel process for preparing aBOS-Na Form I. The present invention further provides a process ofpreparing a BOS-Na Form I, comprising the steps of: 1) preparing amixture of chlorosulfonic acid in an organic solvent; 2) adding BOA tothe mixture; 3) treating the mixture with NaOH to raise pH; and 4)isolating the BOS-Na Form I.

[0068] The present invention provides a novel process for preparing aBOS-Na Form I. The present invention further provides a process ofpreparing a BOS-Na Form I, comprising the steps of: 1) preparing amixture of an anhydride and sulfuric acid to form acyl-sulfate in thepresence of an organic solvent; 2) adding BOA to the mixture; 3)treating the mixture with NaOH to raise pH; 4) cooling the mixture toform a precipitate; 5) drying the precipitate; and 6) keeping the dryprecipitate at room temperature to obtain the BOS-Na Form I.

[0069] The present invention provides a novel process for preparing aBOS-Na Form II. The invention further provides a process of preparing aBOS-Na Form II, comprising the steps of: 1) preparing a mixture of ananhydride and sulfuric acid to form acyl-sulfate in the presence ofethyl acetate; 2) adding BOA to the mixture; and 3) treating the mixturewith NaOH to raise pH; 4) cooling the mixture to form a precipiate; and5) drying the preciptate at 80° C. to obtain the BOS-Na Form II.

[0070] The present invention provides a novel process for preparingBOS-Na Form III. The present invention further provides a method ofpreparing a BOS-Na Form III, comprising the steps of: 1) preparing amixture of an anhydride and sulfuric acid to form acyl-sulfate in thepresence of toluene; 2) adding BOA to the mixture; 3) treating themixture with NaOH to raise pH; 4) cooling the mixture to form aprecipitate; and 5) drying the preciptate at 80° C. to obtain the BOS-NaForm III.

[0071] The present invention provides a novel process for preparing aBOS-Na Form V. The present invention further provides a method ofpreparing a BOS-Na Form V, comprising the steps of: 1) preparing amixture of an anhydride and sulfuric acid to form acyl-sulfate; 2)adding BOA to the mixture; 3) treating the mixture with NaOH to raisepH; 4) cooling the mixture to form a precipitate; and 5) drying thepreciptate at about 85° C. to obtain the BOS-Na Form V.

[0072] The present invention provides a novel process for preparingBOS-Ba Form I. The present invention further provides a method ofpreparing a BOS-Ba Form I, comprising the steps of: 1) preparing amixture of chlorosulfonic acid and an organic solvent; 2) adding BOA tothe mixture; 3) treating the mixture with Ba(OH)₂, and 4) isolating theBOS-Ba Form I.

[0073] The present invention provides a novel process for preparing aBOS-Ca Form I. The present invention further provides a method ofpreparing a BOS-Ca Form I, comprising the steps of: 1) preparing amixture of chlorosulfonic acid and an organic solvent; 2) adding BOA themixture; 3) treating the mixture with Ca(OH)₂; and 4) isolating theBOS-Ca Form I.

BRIEF DESCRIPTION OF THE DIAGRAMS

[0074]FIG. 1 depicts the X-ray Powder Diffraction (XRD) Pattern forBOS-Na monohydrate novel Form I.

[0075]FIG. 2 depicts the Furier Transform Infra Red Spectroscopy (FTIR)spectrum of BOS-Na novel Form I.

[0076]FIG. 3 depicts the Differential Thermal Gravimetry (DTG) of BOS-Nanovel Form I.

[0077]FIG. 4 depicts the X-ray Powder Diffraction (XRD) Pattern forBOS-Na novel Form II.

[0078]FIG. 5 depicts the Furier Transform Infra Red Spectroscopy (FTIR)spectrum of BOS-Na novel Form II.

[0079]FIG. 6 depicts the Differential Thermal Gravimetry (DTG) of BOS-Nanovel Form II.

[0080]FIG. 7 depicts the X-ray Powder Diffraction (XRD) Pattern forBOS-Na novel Form III.

[0081]FIG. 8 depicts the Furier Transform Infra Red Spectroscopy (FTIR)spectrum of BOS-Na novel Form III.

[0082]FIG. 9 depicts the Differential Therinal Gravirnetry (DTG) ofBOS-Na novel Form III.

[0083]FIG. 10 depicts the X-ray Powder Diffraction (XRD) Pattern forBOS-Na novel Form V.

[0084]FIG. 11 depicts the Furier Transform Infra Red Spectroscopy (FTIR)spectrum of BOS-Na novel Form V.

[0085]FIG. 12 depicts the Differential Scanning Calorimetry (DSC) ofBOS-Na novel Form V.

[0086]FIG. 13 depicts the Thermal Gravimetric Analysis (TGA) thermogramof BOS-Na novel Form V.

[0087]FIG. 14 depicts the X-ray Powder Diffraction (XRD) Pattern forBOS-Ba novel Form I.

[0088]FIG. 15 depicts the Furier Transform Infra Red Spectroscopy (FTIR)spectrum of BOS-Ba novel Form I.

[0089]FIG. 16 depicts the Differential Thermal Gravimetry (DTG) ofBOS-Ba novel Form I.

[0090]FIG. 17 depicts the X-ray Powder Diffraction (XRD) Pattern forBOS-Ca novel Form I.

[0091]FIG. 18 depicts the Differential Thermal Gravimetry (DTG) ofBOS-Ca novel Form I.

[0092]FIG. 19 depicts the X-ray Powder Diffraction (XRD) Pattern forBOS-H monohydrate novel Form I.

[0093]FIG. 20 depicts the Differential Thermal Gravimetry (DTG) of BOS-Hmonohydrate novel Form I.

DETAILED DESCRIPTION OF THE INVENTION

[0094] As used throughout the text, the following abbreviations areused: benzisoxazole acetic acid (BOA); benzisoxazole-methane-sulfonicacid (BOS); sodium salt of benzisoxazole-methane-sulfonic acid (BOS-Na);calcium salt of benzisoxazole-methane-sulfonic acid (BOS-Ca); bariumsalt of benzisoxazole-methane-sulfonic acid (BOS-Ba); sulfuric acid(H₂SO₄), chlorosulfonic acid (ClSO₃H), disulfonation product (S-BOS);tertiary-butyl alcohol (t-BuOH).

[0095] As used herein, the term “substantially free” refers to less than2-5%. Room temperature refers to ambient temperature.

[0096] As used herein, the term “TGA” refers to thermogravimetricanalysis. The Karl Fisher assay for determining water content is wellknown and is described in Pharmacopeial Form, Vol. 24, No. 1, p.5438(Januart-February 1998). Such an assay permits the determination ofwater content of a crystal form based on the Loss on Drying Method. TGAis a measure of the thermally induced weight loss of a material as afunction of the applied temperature.

[0097] As used herein, the term “FTIR” refers to Furier Transform InfraRed Spectroscopy. FTIR is a well-known spectroscopy analysis in whichabsorption of IR energy by the sample results from transitions betweenmolecular vibrational energy levels. FTIR is used, in modem practice,mainly for identification of functional groups in the molecule. However,different polymorphic forms also show differences in FTIR. The FTIRspectra were collected using Diffuse Reflectance Technique; scanningrange: 4000-400 cm⁻¹, 16 scans, resolution: 4.0 cm⁻¹.

[0098] The present invention relates to more convenient methods forsulfonation of benzisoxazole acetic acid (BOA). The sulfonation processinvolves a reaction that does not use dioxane and eliminates the problemof the waste.

[0099] The present sulfonation method relates to the sulfonationreaction of benzisoxazole acetic acid using chlorosulfonic acid inorganic solvents like dichloroethane, dichloromethane, toluene, ethyleneglycol-dimethylether or heptane using a slight excess of the sulfonatingreagent. Under such conditions, the sulfonation reaction is selective.

[0100] The present sulfonation reaction solvent may be a polar solventlike ethyl-acetate, dichloroethane, t-BuOH, or a non-polar solvent likehexanes, heptane, cyclohexane, toluene, dichlorobenzene or mixturethereof.

[0101] The present invention has the advantage of the sulfonationreaction using chlorosulfonic acid wherein the reaction is selective andproceeds mainly in the alpha position of benzisoxazole acetic acid. Thedisulfonated product is obtained at a level of about 2-5%.

[0102] The present invention also provides a process for preparingbenzisoxazole methane sulfonic acid (BOS) employing acyl-sulfates or insitu prepared acyl-sulfates. In situ prepared acyl-sulfates may beobtained from anhydrides and sulfuric acid, acyl-halides and sulfuricacid, or carboxylic acids and sulfuric acid; all organic acids includingfatty acids may react in this way.

[0103] A more preferred sulfonation process involves the use of theacyl-sulfates obatined from anhydrides and H₂SO₄ or acyl-halide andH₂SO₄. Examples of acyl-sulfates of a practical interest includeacetyl-sulfate (obtained from Ac₂O/H₂SO₄ or acetylchloride/H₂SO₄),propionyl-sulfate, butyryl-sulfate or other acyl-sulfate (obtained inthe same manner from the corresponding anhydride or acyl-halide andH₂SO₄) which are more economics and more easy to handle.

[0104] The more preferred method uses acetic anhydride and sulfuric acid(H₂SO₄). The more preferred sulfonating reagent “anhydride acetic/H₂SO₄”is economic, easy for handling, and excludes the use of dioxane.

[0105] The sulfonation process using acyl-sulfates is even moreselective than that of chlorosulfonic acid in organic solvent. Theselective sulfonation proceeds preferentially in the alpha position andthe disulfonated side-product is obtained at a low level up to 1%.

[0106] The sulfonation process for the Ac₂O/H₂SO₄ involves a reactionthat is performed in polar and non-polar solvents. The polar solventsinclude ethylacetate, ethylcellosolve, methylcellosolve, dichloroethane,dichloromethane, chloroform or mixture thereof and the like. Thenon-polar solvents include toluene, heptane, hexanes, alkanes ormixtures thereof and the like.

[0107] We observed that the product of the sulfonation reaction in thezonisamide process may be obtained with a variable water content. Thisobservation is valid for BOS-H and its salts also.

[0108] The present invention provides new crystal forms of BOS. Thepolymorphic modification of this zonisamide intermediate are chemicallyidentical, but exhibit differences in their physical properties such asX-Ray Diffractrogram, Furier Transform Infra Red Spectroscopy and etc.Differences in mechanical behavior or in the dissolution properties ofdifferent polymorphic modifications can significantly influence the easeof processing or the bioavailability of these compounds. It is desirableto obtain various crystal or polymorphic forms of zonisamideintermediates.

[0109] We observed BOS is a hygroscopic compound. We further observedthat BOS-H is a more hygroscopic compound than its alkaline orearth-alkaline salts. Practically, it is recommended to isolate theproduct as salt rather than the free sulfonic acid.

[0110] BOS-H and its salts are readily soluble in water and this makesdifficult their separation from the reaction mixture.

[0111] However, the salts of sulfonic acid are less water-soluble thanthe inorganic salts and it is preferable to proceed to the conversion ofsulfonic acid into its salt (sodium, calcium or barium salt) and toisolate them by salting out with an inorganic salt.

[0112] The salts of BOS having a practical interest include generallyalkaline salts and earth-alkaline salts. Examples of BOS salts includesodium (Na), potassium (K), calcium (Ca), barium (Ba), and Magnesium(Mg). In general, BOS is a strong acid having approximately the samestrength as H₂SO₄ and can forms salts with various cations includingsilver (Ag), cadium (Ca), zinc (Zn), mercury (Hg), and aluminium (Al).

[0113] The present invention further provides a crystalline form ofbenzisoxazole methane sulfonic acid wherein the metal cation is selectedfrom sodium, calcium, barium, potassium, magnesium, lithium, manganese,cobalt, iron, copper, nickel, zinc, and silver.

[0114] BOS-H and its sodium (Na-), calcium (Ca-) or barium (Ba-) saltsare usually obtained from the reaction with 1-2% water content but theycan absorb water from the medium until the hydrate is obtained.

[0115] The present invention is described in details with reference toexamples. The present invention is by no means restricted to thesespecific examples. The experiments of the invention are summarized inthe following table. SYNTHESIS OF THE ZONISAMIDE INTERMEDIATE (BOS)Reaction Purity profile HPLC, conditions: Sample % Area, Ex. Nr.Reagent, eq. nr/solvent Temp., time type BOS-Na S-BOS BOA TN 2410 1.3eq. ClSO₃H/dichloro- Reflux, 1.5 hours Reaction 90 5.4 0.4 ethanemixture Isolated 99.8 0.15 product TN 2404 1.3 eq. 50° C., 20 hoursReaction 58 34 ClSO₃H/Ethylenglycol- mixture dimethyl-ether Isolatedn.a. n.a. n.a. product TN 2409 1.3 eq. 65° C., 3 hours Reaction 95 1.83.1 ClSO₃H/Heptane + dichloro- mixture ethane Isolated 99.5 0.15 0.4product TN 2412 1.7 eq. ClSO₃H/Toluene Reflux, 20 hours Reaction 63.5 332 mixture TN 2394 1.3 eq. Ac₂O/H₂SO₄/dichloro- 75° C., 2 hours Reaction85.5 0.8 0.1 ethane mixture TN 2396 2.7 eq. Ac₂O/H₂SO₄/Tol. Reflux, 9hours Reaction 83.4 n.d. 10.7 mixture Isolated 92.4 n.d. 4.5 product TN2400 1.3 eq. Ac₂O/H₂SO₄/Heptane 90° C., 1 hours Isolated 98.4 n.d. 1.5product TN 2402 1.3 eq. Ac₂O/H₂SO₄/dichloro- ˜100° C., 1.5 hour Reaction98.5 0.2 0.2 benzene mixture Isolated 99.7 n.d. 0.2 product TN 2431 1.3eq. Ac₂O/H₂SO₄/EtOAc ˜90° C., 4 hours Reaction 99.2 0.5 n.d. mixtureIsolated 100 product TN 2430 1.3 eq. Ac₂O/H₂SO₄/EtOAc ˜90° C., 4 hoursReaction 99.1 0.5 n.d. reverse addition of the mixture reagents: H₂SO₄added to the Isolated 100 reaction mixture product

[0116] Experimental Procedures

EXAMPLE 1 Preparation of BOS-Na: Ac₂O/H₂SO₄ in Ethyl-acetate

[0117] In a 250 mL reactor, equipped with thermometer, mechanicalstirrer and condenser was charged ethyl acetate (80 mL),H₂SO₄, 98% (22grams, 1.3 eq.) and acetic anhydride (23 grams, 1.3 eq.) and the mixturewas cooled to −5° C.

[0118] To the above mixture, BOA was added (20 grams, 1 eq.). Thereaction was then heated to reflux and the reflux was continued for 4hours. After the reaction completion the reaction mixture was cooled tothe room temperture and aqueous NaOH (10%) was added (120 mL). Uponstirring, the product precipitates as sodium salt. After 2 hours theproduct was filtrated, washed with ethyl acetate (2×25 mL) and dried invacuum-oven at ˜80° C. The yield was 20.33 grams BOS-Na having 100%purity by HPLC).

EXAMPLE 2 Preparation of BOS-Na: Ac₂O/H₂SO₄ in Ethyl Acetate byDrop-Wise Addition of H₂SO₄

[0119] In a 250 mL reactor, equipped with thermometer, mechanicalstirrer and condenser was charged ethyl acetate (80 mL), aceticanhydride (23 grams, 1.3 eq.) and BOA (20 grams, 1 eq.). The mixture wascooled to above −5° C.

[0120] Maintaining the temperature below 0° C., H₂SO₄, 98% (22 grams,1.3 eq.) was added drop-wise (the addition required about 20 min.). Thenthe reaction mixture was stirred at reflux for 4 hours. When thereaction was completed the mixture was cooled to room temperature andaqueous NaOH (10%) was added (120 mL). After 2 hours stirring at roomtemperature, the reaction product was filtrated, washed with ethylacetate (2×25 mL) and dried in vacuum-oven ˜80° C. The yield was 20.21grams of BOS-Na that has a 100% purity.

EXAMPLE 3 Preparation of BOS-Na: Ac₂O/H₂SO₄ in Toluene

[0121] In a 100 mL three necked flask, equipped with thermometer,condenser and mechanical stirrer was charged toluene (40 mL), H₂SO₄,98%(2 mL, 1.3 eq.) and acetic anhydride (3.5 mL, 1.3 eq.) at roomtemperature.

[0122] Then, benzisoxazole acetic acid (BOA) was added (5 grams) and thereaction mixture was heated to reflux. The reflux was continued forabout 4.5 hours. To the chilled reaction mixture, more reagent was added(2 mL H₂SO₄, 98% and 3.5 mL acetic anhydride) and the heating wascontinued for additional 4 hours. After cooling of the reaction mixtureto room temperature, ice was added and the mixture was stirred. Theorganic phase was discarded and to the aqueous phase solid NaOH wasadded (7.5 grams). The product precipitates upon cooling at ˜5° C.; thesolid was filtrated, washed with toluene and dried in vacuum-oven at˜80° C. The yield was 7.6 g BOS-Na with 92.4% purity on HPLC.

EXAMPLE 4 Preparation of BOS-Na: ClSO₃H in Dichloroethane

[0123] In a 100 mL three necked flask, equipped with thermometer,condenser and mechanical stirrer was charged dichloroethane (25 mL), 2.5mL ClSO₃H (1.3 eq.), and BOA (5 grams). The reaction mixture was heatedat reflux for 1.5 hours.

[0124] Water was added (30 mL) and the phases were separated. To theaqueous phase, solid NaOH was added (3.5 grams) and the product wasfiltrated, washed with dichloroethane (2×10 mL) and dried in cooling at5° C. The solid was filtrated, washed with toluene and dried in vacuumto affords 5.11 grams BOS-Na, 98.5% purity on HPLC.

EXAMPLE 5 Preparation of Zonisamide from BOS-Na

[0125] In a 250 mL three necked flask, equipped with thermometer,mechanical stirrer and condenser was charged POCl₃ (60 mL) and BOS-Na(19 grams). The reaction mixture was heated to reflux and the reflux wasmaintained for three hours. The excess of POCl₃ was distilled and to theobtained residue was added ethyl-acetate. After a few minutes ofstirring, the solids were filtered and washed with ethyl-acetate. Thesolution of ethyl-acetate contains the product 1,2-benzisoxazole methanesulfonyl chloride.

[0126] To the chilled solution of the product in ethyl-acetate (˜5° C.),ammonia gas was bubbled until the solution reached pH 12. The solidswere filtered and washed with ethyl-acetate. The combined solutions ofethyl-acetate were evaporated on rotovapor to afford the productzonisamide (14.88 grams).

[0127] Crystalline Forms of the Zonisamide Intermediate (BOS):Characterization

[0128] Novel Crystal Forms of BOS-Na

[0129] BOS-Na Novel Form I

[0130] BOS-Na monohydrate novel form I was characterized by X-Ray PowderDiffraction (XRD), Furier Transform Infra Red Spectroscopy (FTIR),Differential Thermal Gravimetry (DTG), and Karl-Fischer titration (KF).

[0131] XRD

[0132] BOS-Na monohydrate novel form I is characterized by the followingX-Ray Diffraction main peaks at about 5.0, 15.7, 16.5, 17.3, 18.6, 19.1,19.7, 21.5, 22.8, 23.2, 23.5 and 24.3±0.2 degrees two theta. The mostcharacteristic XRD peaks at about 5.0, 17.3, 18.0, 18.6, 19.73±0.2degrees two theta.

[0133] X-Ray Powder Diffraction pattern is given in FIG. 1.

[0134] FTIR

[0135] FTIR spectrum of BOS-Na novel form I is characterized by thefollowing peaks at about 3546, 3485, 3440, 1612, 1513, 1439, 1410, 1382,1234, 1199, 1048, 918, 855, 760, 669 and 593 cm⁻¹. The mostcharacteristic FTIR peaks at about 593, 669, 1641, 3440, 3485 and 3546cm⁻¹.

[0136] FTIR spectrum of BOS-Na novel form I is given in FIG. 2

[0137] DTG

[0138] The combined DTA and TGA profiles of Bos-Na form I ischaracterized by an endothermic peak at about 100° C. The TGA curveshows a weight loss step of about 7% in this temperature range. Thisweight loss step is due to water released out of the sample.

[0139] DTG profile is given in FIG. 3.

[0140] KF

[0141] Water content measured by Karl-Fischer (KF) method is inagreement with TGA weight loss step and is about 7%. This water contentis coincident with the expected water content of monohydrate.

[0142] BOS-Na Novel Form II

[0143] BOS-Na novel form II was characterized by X-Ray PowderDiffraction (XRD), Furier Transform Infra Red Spectroscopy (FTIR) andDifferential Thermal Gravimetry (DTG).

[0144] XRD

[0145] BOS-Na novel form II is characterized by the following X-RayDiffraction main peaks at about 5.3, 15.9, 16.6, 21.3 and 26.7±0.2degrees two theta. The most characteristic XRD peaks are at about 5.3,16.6, 21.3, and 26.7±0.2 degrees two theta.

[0146] X-Ray Powder Diffraction pattern is given in FIG. 4.

[0147] FTIR

[0148] FTIR spectrum of BOS-Na novel form II is characterized by thefollowing peaks at about 3597, 3535, 3496, 3067, 2998, 2951, 1606, 1516,1438, 1382, 1213, 1064, 1055, 743, 663, 588, 541 and 522 cm⁻¹. The mostcharacteristic FTIR peaks are at 3571 and 3597 cm⁻¹.

[0149] FTIR spectrum of BOS-Na novel form II is given in FIG. 5.

[0150] DTG

[0151] DTG profile is given in FIG. 6.

[0152] DTG profile of BOS-Na novel form II is characterized by threeendothermic peaks at about 243, 265 and 278° C. The sharp weight loss inthis temperature range is due to decomposition of the sample.

[0153] BOS-Na Novel Form III

[0154] BOS-Na novel form III was characterized by X-Ray powderdiffraction (XRD), Furier Transform Infra Red Spectroscopy (FTIR) andDifferential Thermal Gravimetry (DTG).

[0155] XRD

[0156] BOS-Na novel form III is characterized by the following X-RayDiffraction main peaks at about 5.0, 5.3, 15.7, 17.8 and 21.4±0.2degrees two theta. The most characterisitc XRD peaks are at about 5.0,5.3, and 17.8±0.2 degrees two theta. X-Ray Powder Diffraction pattern isgiven in FIG. 7.

[0157] FTIR

[0158] FTIR spectrum of BOS-Na novel form III is characterized by thefollowing peaks at about 3604, 3495, 3067, 2998, 2951, 1605, 1516, 1438,1382, 1215, 1136, 1065, 1052, 777, 747, 696, 588 and 521 cm⁻¹. The mostcharacteristic FTIR peaks are at about 696, 812, 1065 and 3604 cm⁻¹.

[0159] FTIR spectrum of BOS-Na novel form III is given in FIG. 8.

[0160] DTG

[0161] DTG profile is given in FIG. 9.

[0162] DTG profile of BOS-Na novel form III is characterized by anendothermic peak at about 233° C. The sharp weight loss in thistemperature range is due to decomposition of the sample.

[0163] BOS-Na Novel Form V

[0164] BOS-Ba novel form V was characterized by X-Ray Powder Diffraction(XRD), Furier Transform Infra Red Spectroscopy (FTIR), DifferentialScanning Calorimetry, and Thermal Gravimetric Analysis (TGA).

[0165] XRD

[0166] XRD analysis were performed X-Ray powder diffractometer, Scintag,variable goniometer, Cu-tube, solid state detector. Sample holder: Around standard aluminum sample holder with round zero background quartzplate. Scanning parameters: Range: 2-40 degrees two theta. Continuousscan rate: 3 deg./min.

[0167] BOS-Na novel form V is characterized by the following X-RayDiffraction main peaks at about 6.7, 10.9, 16.2, 21.0, 21.2 and 22.2±0.2degrees two theta.

[0168] X-Ray Powder Diffraction pattern is given in FIG. 10.

[0169] FTIR

[0170] FTIR spectrum was collected on Perkin-Elmer Spectrum One FTIRspectrometer using Diffused Reflectance technique. Scanning range:400-4000 cm⁻¹, number of scans: 16, resolution: 4.0 cm⁻¹.

[0171] FTIR spectrum of BOS-Na novel form V is characterized by thefollowing peaks at about 753, 793, 1055, 1587, 3520 and 3601 cm⁻¹.

[0172] FTIR spectrum of BOS-Na novel form V is given in FIG. 11.

[0173] DSC

[0174] DSC 821^(e), Mettler Toledo instrument was used for the DSCanalysis. Sample weight: 3-5 mg. Heating rate: 10° C./min. Number ofholes in the crucible:3.

[0175] DSC profile is characterized by two overlapped endothermic peaksat about 164° C.

[0176] DSC profile of BOS-Na noevl form V is given in FIG. 12.

[0177] TGA

[0178] Mettler TG50 instrument was used for the TGA analysis. Heatingrate: 10° C./min. Nitrogen flow: 40 ml/min.

[0179] TGA thermogram shows LOD value of about 2% in a temperature rangeof up to 190° C.

[0180] TGA thermogram of BOS-Na form V is given in FIG. 13.

[0181] Novel Crystal Form of BOS-Ba

[0182] BOS-Ba Novel Form I

[0183] BOS-Ba novel form I was characterized by X-Ray Powder Diffraction(XRD), Furier Transform Infra Red Spectroscopy (FTIR) and byDifferential Thermal Gravimetry (DTG).

[0184] XRD

[0185] BOS-Ba novel form I is characterized by the following X-RayDiffraction main peaks at about 5.2, 10.4, 12.0, 13.8, 15.6, 17.0, 23.9and 25.4±0.2 degrees two theta.

[0186] X-Ray Powder Diffraction pattern is given in FIG. 14.

[0187] FTIR

[0188] FTIR spectrum of BOS-Ba is characterized by the following peaksat about 3544, 3491, 2985, 2943, 1626, 1610, 1509, 1437, 1383, 1369,1223, 1209, 1175, 1153, 1055, 1043, 911, 869, 752, 651, 603, 543 and 511cm⁻¹.

[0189] FTIR spectrum is given in FIG. 15.

[0190] DTG

[0191] DTG profile of BOS-Ba novel form I is characterized by anendothermic peak at about 200° C. A weight loss step of about 3.5% isobserved in this temperature range.

[0192] DTG thermogram of BOS-Ba novel form I is given in FIG. 16.

[0193] Novel Crystal Form of BOS-Ca

[0194] BOS-Ca Novel Form I

[0195] BOS-Ca novel form I was characterized by X-Ray Powder Diffraction(XRD) and by Differential Thermal Gravimetry (DTG).

[0196] XRD

[0197] BOS-Ca novel form I is characterized by the following X-RayDiffraction main peaks at about 5.4, 11.7, 16.0, 16.7, 17.7, 18.1, 19.1,20.8, 24.5, 24.9 and 29.2±0.2 degrees two theta.

[0198] X-Ray Powder Diffraction pattern is given in Fg. 17.

[0199] DTG

[0200] DTG profile of BOS-Ca novel form I is characterized by twoendothermic peaks at about 137 and 165° C. The LOD up to 200° C. isabout 7.6%.

[0201] DTG themogram of BOS-Ca novel form I is given in FIG. 18.

[0202] Novel Crystal Form of BOS-H

[0203] BOS-H Novel Form I

[0204] BOS-H monohydrate novel form I was characterized by X-Ray PowderDiffraction (XRD), by Differential Thermal Gravimetry (DTG) and byKarl-Fischer titration (KF).

[0205] XRD

[0206] BOS-H novel monohydrate novel form I is characterized by thefollowing X-Ray Diffraction main peaks at about 13.8, 14.4, 17.4, 17.8,21.8, 22.2, 25.8, 27.8±0.2 degrees two theta.

[0207] X-Ray Powder Diffraction pattern is given in FIG. 19.

[0208] DTG

[0209] DTG profile of BOS-H monohydrate novel form I is characterized bytwo endothermic peak at about 120 and 175° C. A weight loss step ofabout 9% is observed in this temperature range.

[0210] DTG thermogram of BOS-H monohydrate novel form I is given in FIG.20.

[0211] KF

[0212] Water content of BOS-H novel form I as was measured by KFtitration is about 7.6%. This value is coincident with the expectedwater content for monohydrate form.

[0213] The invention will be better understood from the followingexperimental details. These examples are provided to illustrate specificembodiments of the present invention but they are not intended to belimiting in any way.

[0214] Experimental Procedure: Preparation of Crystalline Forms of BOS

[0215] Preparation of BOS-H Form I

[0216] The solution of chlorosulfonic acid (13 ml, 25.5 mmol) inmethylene chloride (100 ml) was cooled to ˜−10° C. Dioxane (22.5 grams,25.5 mmol) was added at this temperature followed by the addition of BOA(30 grams, 16.9 mmol). The obtained slurry was than heated at reflux for2.5 hours. The reaction mixture was stirred at room temperature overnight and after this was held with ice.

[0217] The aqueous phase was extracted with methylene chloride and thenevaporated to dryness on rotavapor. The solid was dried for two days at60° C. and for ˜16 hours at 100° C. The product is BOS-H Form I (KF2.8%).

[0218] Preparation of BOS-Na Form I

[0219] To the chilled solution (0° C.) of chlorosulfonic acid (136grams, 1.167 mol) in ethyl acetate (400 ml) was added drop-wise dioxane(103 grams, 1.169 mol) followed by the addition of BOA (180 grams, 1.017mol). The mixture was than heated at about 55° C. for about 16 hours.After the reaction completion, the mixture has been cooled to roomtemperature and ice-water was added. The aqueous phase was treated withaqueous NaOH until pH 10.

[0220] The product was isolated by evaporation to dryness of the aqueoussolution and n-BuOH. The obtained solid was than dried in oven at 80° C.BOS-Na (271 grams) was obtained; the solid does not contain water (KF0.002%). BOS-Na dry was kept in a closed bottle at room temperature.After about 5 months the KF analysis (7.3%) indicates the formation ofhydrate-BOS-Na Form I.

[0221] Preparation of BOS-Na Form I

[0222] To the solution of BOA (5 grams, 28.25 mmol) in ethyl acetate (30ml) was added acetic anhydride (3.75 grams, 36.73 mmol) and sulfuricacid 98% (3.6 grams, 36.73 mmol). During the addition of sulfuric acidthe temperature reached ˜30° C. Then the reaction mixture had beenheated at reflux for 1.5 hour.

[0223] More sulfonating reagent was added (2.1 grams acetic anhydrideand 2 grams sulfuric acid) and the reflux was continued for more onehour. The reaction mixture was then cooled to room temperature and heldwith aqueous 10% NaOH (32 ml). The product precipitates upon cooling to˜5° C. The solid was washed with ethyl acetate and dried at 80° C. for 2days. The obtained BOS-Na (6.3 grams) contains 1.7% water (by KF). Thissolid was exposed to the laboratory humidity for one week; the obtainedsolid is BOS-Na Form I.

[0224] Preparation of BOS-Na Form II

[0225] The solution of acetic anhydride (3.75 grams, 36.73 mmol) andsulfuric acid 98% (3.6 grams, 36.73 mmol) in ethyl acetate (30 ml) hasbeen cooled to −5° C. BOA (5 grams, 28.25 mmol) was added and thereaction mixture had been heated at reflux for ˜3 hours.

[0226] After cooling to room temperature the reaction mixture was heldwith aqueous 10% NaOH and cooled to ˜5° C. to precipitate the product;the solid was dried for 2 days in oven at 80° C. BOS-Na (4.9 grams) (KF1.83%) is BOS-Na Form II.

[0227] Preparation of BOS-Na Form III

[0228] The solution of acetic anhydride (5.75 grams, 56.32 mmol) andsulfuric acid 98% (5.5 grams, 56.12 mmol) in toluene (30 ml) was cooledto ˜0° C. BOA was added (5 grams, 28.25 grams) and the reaction mixturewas heated at reflux for 5 hours. More sulfonating reagent was added (3grams acetic anhydride and 2.9 grams sulfuric acid) and the reflux wasmaintained for one additional hour.

[0229] The reaction mixture was cooled to room temperature and treatedwith NaOH pearls to precipitate the product upon cooling. The solid waswashed with toluene, filtrated and dried at 80° C. for two days. Theproduct is BOS-Na Form III.

[0230] Preparation of BOS-Na Form V

[0231] The crystalline form was obtained during the production of BOS-Nain industrial scale. The preparation of BOS-Na is the laboratoryprocedure adapted to the large scale.

[0232] To the chilled (0° C.) solution of acetic anhydride (1.3 eq.) andBOA in ethylacetate, H₂SO₄ (1.3 eq.) was added drop-wise.

[0233] The reaction mixture was heated at reflux and then stirred atreflux until the reaction completion (˜5 hours). After this, the mixturewas cooled to ˜25° C. and treated with NaOH. Th reaction productprecipitatd on cooling to ˜5° C. The solid was filtrated and washed withethylacetate.

[0234] The wet material obtained according to this procedure in theindustrial batch was dried in an industrial drier: Vacuum: 30 mm HgTemperature in the jacket: 85° C. Mechanical stirring Several days untilthe water content Time: was less than 1.5%.

[0235] Preparation of BOS-Ba Form I

[0236] To the chilled solution of chlorosulfonic acid (13 ml, 19.5 mmol)in methylene chloride. 10 ml dioxane (17.25 grams, 16.9 mmol) and BOA(30 grams, 16.9 mmol) were added. The reaction mixture was heated atreflux for 4.5 hours.

[0237] After this the reaction mixture was cooled to room temperatureand ice was added. The aqueous phase was extracted with methylenechloride and then held with Ba(OH)₂ (56 grams); the solid was filtrated,washed with water and dried in oven at 100° C. for 5 hours. The productis BOS-Ba Form I.

[0238] Preparation of BOS-Ca Form I

[0239] To the chilled at (−5° C.) solution of chlorosulfonic acid (13ml, 19.5 mmol) in methylene chloride (100 ml) dioxane (17.2 grams, 19.5mmol) and BOA (30 grams, 16.9 mmol) were added. Then the reactionmixture was heated at reflux for 5 hours.

[0240] After the reaction completion, ice was added to the cooledreaction mixture and the aqueous phase was treated with Ca(OH)₂ until pH12. The product precipitate after stirring for ˜16 hours. The solid wasfiltrated, washed with water and then with hexane and dried in oven at60° C. The product is BOS-Ca Form I.

[0241] From the above it is clear that the invention providescrystalline forms of benzisoxazole methane sulfonic acid (BOS-H) and itssalts (BOS-Na, BOS-Ca, BOS-Ba). The present invention further providesthe BOS in its acid form and BOS as salts, both represent intermediatesin the preparation of zonisamide.

[0242] It is contemplated that various modifications of the describedmodes of carrying out the invention will be apparent to those skilled inthe art without departing from the scope and spirit of the invention.

What is claimed is:
 1. A process for preparing an intermediate ofzonisamide, comprising the steps of: a) preparing a mixture ofchlorosulfonic acid and an organic solvent; b) adding benzisoxazoleacetic acid to the mixture; c) heating the mixture; and d) isolating theintermediate of zonisamide.
 2. The process according to claim 1, whereinthe intermediate of zonisamide is benzisoxazole methane sulfonic acid.3. The process according to claim 1, wherein the organic solvent isselected from the group consisting of dichloroethane, dichloromethane,ethylene glycol-dimethyl-ether, toluene and heptane.
 4. The processaccording to claim 1, wherein the organic solvent is dichloroethane. 5.The process according to claim 1, wherein the benzisoxazole acetic acidis added to the mixture in a molar ratio of benzisoxazole acetic acid:chlorosulfonic acid of about 1:1.3.
 6. The process according to claim 1,wherein the mixture is heated at a temperature between about 0° C. toabout 70° C.
 7. The process according to claim 1, wherein the isolatingstep further comprises adding water to the mixture.
 8. A process forpreparing an intermediate of zonisamide comprising the steps of: a)preparing an acyl sulfate in a solution; b) adding benzisoxazole aceticacid to the solution wherein the benzisoxazole acid is sulfonated by theacyl sulfate to form the intermediate of zonisamide; c) heating thesolution; and d) isolating the intermediate of zonisamide.
 9. Theprocess according to claim 8, wherein the intermediate of zonisamide isbenzisoxazole methane sulfonic acid.
 10. The process according to claim8, wherein the acyl sulfate is formed by preparing a mixture in asolvent, wherein the mixture is selected from the group consisting of ananhydride and sulfuric acid and acyl-halide and sulfuric acid.
 11. Theprocess according to claim 10, wherein the acyl sulfate is formed insitu.
 12. The process according to claim 10, wherein the anhydride isselected from the group consisting of acetic anhydride, propionicanhydride and buytric anhydride.
 13. The process according to claim 10,wherein the anhydride is acetic anhydride.
 14. The process according toclaim 10, wherein the acyl sulfate comprises acetyl sulfate, propionylsulfate, and butyryl sulfate.
 15. The process according to claim 10,wherein the solvent is selected from the group consisting of a polarsolvent and a non-polar solvent.
 16. The process according to claim 15,wherein the polar solvent is selected from the group consisting ofethylacetate, ethylcellosolve, methylcellosolve, dichloroethane,dichloromethane, chloroform or mixture thereof.
 17. The processaccording to claim 15, wherein the non-polar solvent is selected fromthe group consisting of toluene, heptane, hexane, alkane or mixturethereof.
 18. The process according to claim 15, wherein the solvent isethyl acetate.
 19. The process according to claim 8, wherein thebenzisoxazole acetic acid is added to the mixture in a molar ratio ofbenzisoxazole acetic acid: acyl-sulfate about 1:1 to about 1:1.3. 20.The process according to claim 8, wherein the mixture is heated at atemperature between about 5° C. to about 150° C.
 21. The processaccording to claim 8, wherein the mixture is heated at a temperaturebetween about 5° C. to about 120° C.
 22. The process according to claim8, wherein the mixture is heated at a temperature between about 20° C.to about 80° C.
 23. A process for preparing an intermediate ofzonisamide comprising the steps of: a) preparing a mixture ofbenzisoxazole acetic acid and an anhydride in a solvent to form amixture; b) preparing an acyl sulfate in the mixture wherein thebenzisoxazole acid is sulfonated by the acyl sulfate to form theintermediate of zonisamide; c) heating the mixture; and d) isolating theintermediate of zonisamide.
 24. The process according to claim 23,wherein the acyl sulfate is formed by adding sulfuric aicd drop-wise tothe mixture containing benzisoxazole acetic acid and anhydride. 25.Benzisoxazole methane sulfonic acid as prepared according to a processof claim 1, wherein the benzisoxazole methane sulfonic acid issubstantially free of disulfonated benzisoxazole derivatives. 26.Benzisoxazole methane sulfonic acid as prepared according to a processof claim 8, wherein the benzisozale methane sulfonic acid issubstantially free of disulfonated benzisoxazole derivatives. 27.Benzisoxazole methane sulfonic acid as prepared according to a processof claim 23, wherein the benzisozale methane sulfonic acid issubstantially free of disulfonated benzisoxazole derivatives.
 28. Acrystalline form of benzisoxazole methane sulfonic acid.
 29. Thecrystalline form of benzisoxazol methane sulfonic acid according toclaim 28, wherein the crystalline form is at least one of an acid formor a salt form.
 30. The crystalline form of benzisoxazole methanesulfonic acid according to claim 29, wherein the salt form has a metalcation.
 31. The crystalline form of benzisoxazole methane sulfonic acidaccording to claim 30, wherein the metal cation is selected from thegroup consisting of sodium, calcium, barium, potassium, magnesium,lithium, manganese, cobalt, iron, copper, nickel, zinc, and silver. 32.A crystalline BOS-Na Form I.
 33. A crystalline BOS-Na Form I,characterized by an X-Ray powder diffraction (XRD) having the main peaksat about 5.0, 17.3, 18.0, 18.6, and 19.7±0.2 degrees two theta.
 34. Acrystalline BOS-Na Form I, characterized by an X-Ray powder diffraction(XRD) having the main peaks at about 5.0, 15.7, 16.5, 17.3, 18.6, 19.1,19.7, 21.5, 22.8, 23.2, 23.5 and 24.3±0.2 degrees two theta.
 35. Acrystalline BOS-Na Form I, characterized by a Furier Transform Infra RedSpectroscopy (FTIR) spectrum having the following peaks at about 3546,3485, 3440, 1641, 669 and 593 cm⁻¹.
 36. A crystalline BOS-Na Form I,characterized by a Furier Transform Infra Red Spectroscopy (FTIR)spectrum having the following peaks at about 3546, 3485, 3440, 1612,1513, 1439, 1410, 1382, 1234, 1199, 1048, 918, 855, 760, 669 and 593cm⁻¹.
 37. The crystalline BOS-Na Form I as in claim 32, wherein theBOS-Na Form I has a water content of about 7%.
 38. A crystalline BOS-NaForm II.
 39. A crystalline BOS-Na Form II, characterized by an X-RayPowder Diffraction (XRD) having the main peaks at about 5.3, 16.6, 21.3and 26.7±0.2 degrees two theta.
 40. A crystalline BOS-Na Form II,characterized by an X-Ray Powder Diffraction (XRD) having the main peaksat about 5.3, 15.9, 16.6, 21.3 and 26.7±0.2 degrees two theta.
 41. Acrystalline BOS-Na Form II, characterized by a Furier Transform InfraRed Spectroscopy (FTIR) spectrum having the following peaks at about3597 and 3591 cm⁻¹.
 42. A crystalline BOS-Na Form II, characterized by aFurier Transform Infra Red Spectroscopy (FTIR) spectrum having thefollowing peaks at about 3597, 3535, 3496, 3067, 2998, 2951, 1606, 1516,1438, 1382, 1213, 1064, 1055, 743, 663, 588, 541 and 522 cm⁻¹.
 43. Thecrystalline BOS-Na Form II as in claim 38, wherein the BOS-Na Form IIcontains about 1.8% water.
 44. A crystalline BOS-Na Form III.
 45. Acrystalline BOS-Na Form III, characterized by an X-Ray PowderDiffraction (XRD) having the main peaks at about 5.0, 5.3, and 17.8±0.2degrees two theta.
 46. A crystalline BOS-Na Form III, characterized byan X-Ray Powder Diffraction (XRD) having the main peaks at about 5.0,5.3, 15.7, 17.8 and 21.4±0.2 degrees two theta.
 47. A crystalline BOS-NaForm III, characterized by a Furier Transform Infra Red Spectroscopy(FTIR) spectrum having the following peaks at about 3604, 1065, 812 and696 cm⁻¹.
 48. A crystalline BOS-Na Form III, characterized by a FurierTransform Infra Red Spectroscopy (FTIR) spectrum having the followingpeaks at about 3604, 3495, 3067, 2998, 2951, 1605, 1516, 1438, 1382,1215, 1136, 1065, 1052, 777, 747, 696, 588 and 521 cm⁻¹.
 49. Acrystalline BOS-Na Form V.
 50. A crystalline BOS-Na Form V,characterized by X-Ray Powder Diffraction (XRD) having the main peaks atabout 6.7, 10.9, 16.1, 21.0, 21.2 and 22.2±0.2 degrees two theta.
 51. Acrystalline BOS-Na Form V, characterized by a Furier Transform Infra RedSpectroscopy (FTIR) spectrum having the following peaks at 3601, 3520,1587, 1055, 793 and 753 cm⁻¹.
 52. The crystalline BOS-Na Form V as inclaim 49, wherein the BOS-Na Form V has a water content of less thanabout 1.5%.
 53. A crystalline BOS-Ba Form I.
 54. A crystalline BOS-BaForm I, characterized by the following X-Ray Diffraction main peaks atabout 5.2, 10.4, 12.0, 13.8, 15.6, 17.0, 23.9 and 25.4±0.2 degrees twotheta.
 55. A crysalline BOS-Na Form I, characterized by a FurierTransform Infra Red Spectroscopy (FTIR) spectrum having the followingpeaks at about 3544, 3491, 2985, 2943, 1626, 1610, 1509, 1437, 1383,1369, 1223, 1209, 1175, 1153, 1055, 1043, 911, 869, 752, 651, 603, 543and 511 cm⁻¹.
 56. The crystalline BOS-Ba Form I as in claim 53, whereinthe BOS-Ba Form I has a water content about 3.5%.
 57. A crystallineBOS-Ca Form I.
 58. A crystalline BOS-Ca Form I, characterized by havingthe following X-Ray Diffraction main peaks at about 5.4, 11.7, 16.0,16.7, 17.7, 18.1, 19.1, 20.8, 24.5, 24.9 and 29.2±0.2 degrees two theta.59. A crystalline BOS-H monohydrate Form I.
 60. A crystalline BOS-Hmonohydrate Form I, characterized by having the following X-RayDiffraction main peaks at about 13.8, 14.4, 17.4, 17.8, 21.8, 22.2,25.8, 27.8±0.2 degrees two theta.
 61. The crystalline BOS-H monohydrateForm I as in claim 59, wherein the BOS-H monohydrate Form I has a watercontent about 7.6%.
 62. A process of preparing a BOS-Na Form I,comprising the steps of: 1) preparing a mixture of chlorosulfonic acidin an organic solvent; 2) adding BOA to the mixture; 3) treating themixture with NaOH to raise pH; and 4) isolating the BOS-Na Form I. 63.The process according to claim 62, wherein the pH is raised to about 10.64. The process according to claim 62, wherein the organic solvent isethyl acetate.
 65. A process of preparing a BOS-Na Form I, comprisingthe steps of: 1) preparing a mixture of an anhydride and sulfiric acidto form acyl-sulfate in the presence of an organic solvent; 2) addingBOA to the mixture; 3) treating the mixture with NaOH to raise pH; 4)cooling the mixture to form a precipitate; 5) drying the precipitate;and 6) keeping the dry precipitate at room temperature to obtain theBOS-Na Form I.
 66. The process according to claim 65, wherein thesolvent is ethyl acetate.
 67. The process according to claim 65, whereinthe step 6) is performed for about 5 months.
 68. A process of preparinga BOS-Na Form II, comprising the steps of: 1) preparing a mixture of ananhydride and sulfuric acid to form acyl-sulfate in the presence ofethyl acetate; 2) adding BOA to the mixture; and 3) treating the mixturewith NaOH to raise pH; 4) cooling the mixture to form a precipiate; and5) drying the preciptate at 80° C. to obtain the BOS-Na Form II.
 69. Aprocess of preparing a BOS-Na Form III, comprising the steps of: 1)preparing a mixture of an anhydride and sulfuric acid to formacyl-sulfate in the presence of toluene; 2) adding BOA to the mixture;3) treating the mixture with NaOH to raise pH; 4) cooling the mixture toform a precipitate; and 5) drying the preciptate at 80° C. to obtain theBOS-Na Form III.
 70. A process of preparing a BOS-Na Form V, comprisingthe steps of: 1) preparing a mixture of an anhydride and sulfuric acidto form acyl-sulfate; 2) adding BOA to the mixture; 3) treating themixture with NaOH to raise pH; 4) cooling the mixture to form aprecipitate; and 5) drying the preciptate at about 85° C. to obtain theBOS-Na Form V.
 71. A process of preparing a BOS-Ba Form I, comprisingthe steps of: 1) preparing a mixture of chlorosulfonic acid and anorganic solvent; 2) adding BOA to the mixture; 3) treating the mixturewith Ba(OH)₂; and 4) isolating the BOS-Ba Form I.
 72. The processaccording to claim 71, wherein the organic solvent is methylenechloride.
 73. A process of preparing a BOS-Ca Form I, comprising thesteps of: 1) preparing a mixture of chlorosulfonic acid and an organicsolvent; 2) adding BOA the mixture; 3) treating the mixture withCa(OH)₂; and 4) isolating the BOS-Ca Form I.
 74. The porcess accordingto claim 73, wherein the pH is raised to about
 12. 75. The processaccording to claim 73, wherein the organic solvent is methylenechloride.
 76. The process according to claim 1, wherein the sodium saltof benzisoxazole methane sulfonic acid is thereafter converted to1,2-benzisoxazole-3-methane sulfonamide.
 77. The process according toclaim 8, wherein the sodium salt of benzisoxazole methane sulfonic acidis thereafter converted to 1,2-benzisoxazole-3-methane sulfonamide. 78.The process according to claim 23, wherein the sodium salt ofbenzisoxazole methane sulfonic acid is thereafter converted to1,2-benzisoxazole-3-methane sulfonamide.
 79. 1,2-benzisoxazole-3-methanesulfonamide prepared in accordance with the process of claim
 76. 80.1,2-benzisoxazole-3-methane sulfonamide prepared in accordance with theprocess of claim
 77. 81. 1,2-benzisoxazole-3-methane sulfonamideprepared in accordance with the process of claim
 78. 82. The processaccording to claim 62, wherein the BOS-Na Form I is thereafter convertedto 1,2-benzisoxazole-3-methane sulfonamide.
 83. The process according toclaim 65, wherein the BOS-Na Form I is thereafter converted to1,2-benzisoxazole-3-methane sulfonamide.
 84. The process according toclaim 68, wherein the BOS-Na Form II is thereafter converted to1,2-benzisoxazole-3-methane sulfonamide.
 85. The process according toclaim 69, wherein the BOS-Na Form III is thereafter converted to1,2-benzisoxazole-3-methane sulfonamide.
 86. The process according toclaim 70, wherein the BOS-Na Form V is thereafter converted to1,2-benzisoxazole-3-methane sulfonamide.
 87. The process according toclaim 71, wherein the BOS-Ba Form I is thereafter converted to1,2-benzisoxazole-3-methane sulfonamide.
 88. The process according toclaim 73, wherein the BOS-Ca Form I is thereafter converted to1,2-benzisoxazole-3-methane sulfonamide.